© 2001 American Heart Association, Inc.
Editorial |
TRP Proteins
Novel Therapeutic Targets for Regional Blood Pressure Control?
From the Rammelkamp Center for Education and Research, MetroHealth Medical Center and the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Correspondence to Dr William P. Schilling, Rammelkamp Center, Room R322, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109-1998. E-mail wschilling{at}metrohealth.org
Key Words: Ca2+ channels • store-operated • smooth muscle • adrenergic receptors
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Introduction |
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 Top Introduction References |
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Peripheral vascular resistance is controlled in large part by the sympathetic branch of the autonomic nervous system. In response to sensory input primarily via the vagus nerve, a change in sympathetic outflow alters the tone of the vascular tree via the release of catecholamines from nerve terminals present in the adventitial layer of the vessel wall and from chromaffin cells of the adrenal medulla. Through action at the
1-adrenergic receptor
(1-AR) present on the surface of vascular
smooth muscle cells (SMCs), catecholamines increase contraction,
constrict blood vessels, and, thus, cause an increase in mean arterial
pressure.
As in cardiac and skeletal muscle, a rise in cytosolic free
Ca2+ concentration
([Ca2+]i) triggers
contraction of vascular SMCs. Stimulation of
1-ARs causes an increase in
[Ca2+]i through
several different
mechanisms.1 2
First, 1-AR is a member of the heptahelical
receptor family, which activates phospholipase C (PLC) via a
GTP-binding protein, Gq. Activation of PLC
causes the production of 2 second messengers,
inositol-1,4,5-trisphosphate [Ins(1,4,5)P3]
and diacylglycerol (DAG). Ins(1,4,5)P3 causes
the release of Ca2+ from the endoplasmic
reticulum, resulting in a rapid but transient increase in
[Ca2+]i. DAG is
primarily thought to activate protein kinase C but may also play a more
direct role in activating Ca2+ entry (see
below). In many types of SMCs, receptor stimulation is associated with
activation of nonselective cation channels (NSCCs) that may allow
Ca2+ to enter the cell from the
extracellular space. Perhaps more importantly, the activation of an
NSCC will tend to depolarize the SMC, which in turn will activate
voltage-dependent Ca2+ channels (VDCCs),
allowing additional Ca2+ influx. The
importance of VDCCs to vascular smooth muscle contraction is
underscored by the effectiveness and widespread use of
Ca2+ channel antagonists, such as
nifedipine, in the treatment of hypertension, coronary vasospasm, and
Raynaud’s disease. After activation of PLC,
Ins(1,4,5)P3-induced depletion of the internal
Ca2+ store per se will also activate
Ca2+ entry via so-called store-operated
channels (SOCs). These channels are responsible for
Ca2+ release–activated current
(ICRAC),
which has been best characterized in mast cells and blood lymphocytes.
ICRAC
seems to be a very specific type of SOCs, exhibiting pronounced inward
rectification, a high selectivity for Ca2+
over monovalent cations, anomalous mole-fraction effect, and blockade
by Mg2+ and micromolar concentrations of
lanthanides.3 4
Although
ICRAC is
thought to be a major pathway for Ca2+ entry
after receptor stimulation in many kinds of nonexcitable cells, other
kinds of SOCs with lower selectivity for
Ca2+ have also been reported. In fact, a
recent study5 reports the
measurement of a 3-pS channel in mouse aortic SMCs that poorly
discriminates between monovalent and divalent cations but is activated
by depletion of the internal Ca2+ store.
Furthermore, vascular SMCs seem to have a mechanism by which
Ca2+ store depletion activates
Na+ influx via an
SOC.6 A change in
[Na+]i in the
subplasmalemmal region of the SMC may indirectly influence
[Ca2+]i via the
Na+-Ca2+
exchanger and, under some conditions, dramatically affect global
Ca2+ signaling. Although the contribution of
each of these mechanisms to the overall Ca2+
response undoubtedly will vary in SMCs isolated from different vascular
beds, these receptor-operated channels clearly play a central role in
elevations of
[Ca2+]i, leading to
a long-lasting increase in smooth muscle contraction and mean arterial
pressure.
Although the molecular identity of the
1-AR–activated NSCCs and SOCs present in
vascular smooth muscle has not been determined, the best candidates to
date seem to be the members of the TRP family of ion channels,
originally identified as critical components of phototransduction in
Drosophila. In a mutant fly
called the transient receptor potential mutant
(trp), a defect in the
phototransduction cascade results in an abbreviated
Ca2+ current during prolonged light
stimulation. The protein encoded by
trp (TRP) and another protein
homologous to trp called
trp-like (TRPL) were proposed
to be cation channels activated by an
Ins(1,4,5)P3-dependent mechanism in the
Drosophila photoreceptor
cell.7 Indeed, heterologous
expression studies provided strong support for the hypothesis that
these proteins form channels that can be regulated by PLC-dependent
mechanisms.8 9 10 11 12 13
Full-length human clones with homology to TRP were first independently identified in 1995 by Wes et al14 and Zhu et al.15 Since that time, 7 primary mammalian TRP homologues have been identified.14 15 16 17 18 19 20 21 Interestingly, receptor-mediated changes in [Ca2+]i and whole-cell membrane currents are increased in cells heterologously expressing mammalian TRP3, TRP4, TRP5, TRP6, and TRP7.17 19 20 22 23 24 25 26 Like Drosophila TRP and TRPL, receptor-mediated activation of mammalian TRP channels seems to require phosphoinositide hydrolysis, because this regulation can be blocked by U73122, a specific inhibitor of PLC.20 22 26 27 However, the mechanism by which PLC stimulation is coupled to channel activation remains controversial. Several studies have shown that mammalian TRP channels are not activated by depletion of internal Ca2+ stores, at least when heterologously expressed.17 19 20 22 23 24 25 26 27 28 In contrast, other studies suggest that TRP4 and TRP5 may be SOCs.16 29 30 TRP3, TRP5, and TRP7 may be activated or regulated by a rise in [Ca2+]i per se.19 20 23 Lastly, 3 mammalian TRP homologues, TRP3, TRP6, and TRP7, and Drosophila TRPL seem to be activated by exogenous application of DAG or polyunsaturated fatty acids.20 25 31 However, DAG alone may not be sufficient to explain receptor-mediated activation of these channels. A recent study suggests a role for phosphatidylinositol-4,5-bisphosphate in regulation of TRPL.32
Despite these advances, the lack of specific high-affinity ligands for mammalian TRP has made it difficult to determine the exact physiological role for these channels in cellular signaling. Furthermore, the cell types commonly used for heterologous expression studies seem to endogenously express specific TRP proteins, potentially complicating interpretations because of possible heteromultimeric channel assembly. Heterologous expression of TRP3 in human embryonic kidney (HEK) cells also seems to increase expression of the Ins(1,4,5)P3 receptor,33 raising the possibility that other proteins involved in Ca2+ signaling (eg, endogenous SOCs) may be upregulated or downregulated in response to TRP overexpression. To determine the physiological role of TRP, several investigators have attempted to reduce or eliminate expression of specific TRP proteins using the antisense approach. Transfection of mouse L-cells with a mixture of plasmids containing antisense sequences for 6 different mouse TRP clones essentially eliminated store-operated Ca2+ entry.18 Likewise, studies using antisense oligonucleotides directed against TRP1 or TRP3 suggest that they may play a role in store-operated Ca2+ entry in HEK cells34 and rat submandibular epithelial cells.35 Although these were important pieces of the puzzle, these studies relied on fura-2 fluorescence measurements of either Ca2+ or Ba2+ influx; ie, no electrophysiological comparisons were made between endogenous SOC channels in native cells and heterologously expressed TRP1 or TRP3 channels. Thus, although TRP1 and TRP3 may be involved in store-operated entry, the actual composition of the endogenous channels remains to be determined.
Three studies have provided a comparison between endogenous channels and heterologously expressed TRPs. In pontine neurons, brain-derived nerve growth factor (BDNF), through interaction with TrkB receptors, activates PLC and a nonselective cation current that shares some characteristics with whole-cell currents observed in cells heterologously expressing TRP3.36 Additionally, these studies showed that TRP3 and Trk receptors coimmunoprecipitate from rat brain tissue and that antibodies raised against the cytoplasmic NH2-terminus of TRP3 enhanced whole-cell BDNF currents and activated single BDNF-induced channels in excised patches from pontine neurons. However, the single channels activated by BDNF and the TRP3 antibody differed from heterologously expressed TRP3 channels both in conductance and mean open time. Thus, although TRP3 may be closely associated with the TrkB receptor and may be one component of the BDNF-induced channels, other TRP homologues may contribute to the subunit structure or accessory proteins may be present on the neuronal channels, which convey different biophysical properties. Philipp et al37 considered the contribution of TRP4 to ICRAC currents in a bovine adrenal cortex cell line (SBAC). TRP4, which was originally cloned from bovine adrenal tissue, was found to be abundantly expressed (by Northern blot and in situ hybridization) in the cortex but not the adrenal medulla. SBAC cells also abundantly expressed message for TRP4, but transcripts for TRP1 and TRP3 were also detected by reverse transcriptase–polymerase chain reaction. SBACs exhibited an endogenous ICRAC with characteristics similar to the classical current observed in lymphocytes. Furthermore, these investigators showed that ICRAC and TRP4 protein expression was significantly reduced in SBAC cells transfected with TRP4 cDNA in antisense orientation compared with cells transfected with control vectors. These results provide support for the hypothesis that TRP4 is an important component of SOC in bovine adrenal cortical cells.
In perhaps the most detailed study to date, Inoue et
al,38 in this issue of
Circulation Research, provide
compelling evidence that TRP6 is a requisite component of the
1-AR–activated NSCC in rabbit portal vein
SMCs. On the basis of previous studies, these investigators recognized
that the 1-AR-NSCC and heterologously
expressed TRP6 exhibit distinct similarities at the whole-cell current
level. In particular, they show that mouse TRP6 expressed in HEK cells
is (1) 4 to 5 times more permeable to Ca2+
or Ba2+ than monovalents, (2) activated by
receptor stimulation through a PLC-dependent mechanism, and (3)
unaffected by intracellular application of thapsigargin or
Ins(1,4,5)P3 but activated by
1-oleoyl-2-acetyl-sn-glycerol
and more weakly by the DAG lipase inhibitor RHC80267. Additionally, the
whole-cell TRP6 currents exhibit a distinct current-voltage
(I-V) relationship, with
pronounced outward rectification at positive potentials and inhibition
of inward current at a potential more negative than -50 mV. The
single-channel conductance was in the range of 30 pS, and the
probability of opening was insensitive to membrane potential over the
negative voltage range but increased significantly at positive
potentials, reminiscent of the effect of voltage on single TRPL
channels.39 Overall, the
characteristics of TRP6 expressed in HEK cells were very similar to the
1-AR-NSCC recorded in SMCs. The authors went
on, however, to show that flufenamate enhanced both the
1-AR-NSCC current in SMCs and TRP6 current in
HEKs but inhibited currents observed in mTRP3- and mTRP7-expressing HEK
cells. The respective
K0.5
values for blockade of 1-AR-NSCC and TRP6 by
Cd2+, La3+,
Gd3+, SKF96365, and amiloride were
essentially identical. Thus, 1-AR-NSCC and
TRP6 currents have similar pharmacological profiles. TRP6 mRNA was
abundantly expressed in portal vein tissue and in the isolated SMCs.
TRP1 and TRP3 were also expressed in very small amounts, but TRP4 was
barely detectable, and TRP5 and TRP7 were absent. Immunocytochemistry
using antibodies raised against the COOH-terminal sequence of TRP6
showed staining in isolated SMCs at or near the plasma membrane.
Lastly, incubation of isolated SMCs with TRP6 antisense
oligonucleotides almost completely abolished expression of TRP6 protein
and 1-AR–induced current and
Ba2+ influx in the SMC. Importantly, TRP1
and TRP3 sense or antisense oligonucleotides had no effect on the
responses to 1-AR stimulation. Likewise,
neither TRP6 sense nor antisense had effects on thapsigargin-induced
responses. These results provide strong support for the hypothesis that
TRP6, although not an SOC, is an essential component of the
1-AR-NSCC in rabbit portal vein SMCs and at a
minimum suggest that the composition of the channels recorded in HEK
cells heterologously expressing TRP6 are similar, if not identical, to
the channels in the SMCs.
In conclusion, although TRP transcripts seem to be ubiquitously and differentially expressed across various tissues and cell lines,40 it now seems reasonable to speculate that specific TRP proteins will functionally dominate receptor-mediated responses in specific tissues. Furthermore, the study by Inoue et al38 suggests that TRP6 may be an important target for new drug therapies directed at reducing smooth muscle tone and arterial blood pressure. To the extent that other TRP channels serve similar roles in different blood vessels,41 the goal of developing specific drugs targeted to the vasculature of specific tissues may, for the first time, be a real possibility.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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